WO2023179082A1 - 一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用 - Google Patents

一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用 Download PDF

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WO2023179082A1
WO2023179082A1 PCT/CN2022/135610 CN2022135610W WO2023179082A1 WO 2023179082 A1 WO2023179082 A1 WO 2023179082A1 CN 2022135610 W CN2022135610 W CN 2022135610W WO 2023179082 A1 WO2023179082 A1 WO 2023179082A1
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drug
coating
medical device
water
coating liquid
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PCT/CN2022/135610
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English (en)
French (fr)
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钟伟
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上海以心医疗器械有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices

Definitions

  • the present disclosure relates to the technical field of medical devices, and specifically to a drug-coated medical device and its preparation method and application, drug coating and its application.
  • Macrolides such as sirolimus, everolimus, tacrolimus and zotarolimus have been proven to have good anti-proliferative effects and can be loaded on the surface of intravascular implanted devices.
  • the slow release of time can inhibit the proliferation of vascular smooth muscle cells and reduce restenosis.
  • intravascular implants also brings a series of negative effects. Therefore, people expect that on the one hand, these drugs can be delivered to the diseased blood vessels while opening the occluded or narrowed diseased blood vessels; at the same time, after the device is withdrawn after the treatment, these drugs can stay in the diseased blood vessels for a long enough time. To prevent restenosis.
  • the present disclosure provides a drug-coated medical device that can transfer enough drugs to the blood vessel wall during the time when the drug-coated medical device is in contact with the blood vessel wall, and it can be used for a long time after the drug-coated medical device is withdrawn. A certain drug concentration is still maintained in the blood vessel wall tissue over a period of time.
  • the present disclosure provides a preparation method for drug-coated medical devices, which has the advantages of simple operation, mild conditions, short process flow, time saving, cost reduction, and suitability for mass production.
  • the present disclosure provides the use of a drug-coated medical device as described above in preparing drugs or medical devices for treating atherosclerotic diseases, preventing restenosis, and preventing local tissue hyperplasia.
  • the present disclosure provides a pharmaceutical coating.
  • the present disclosure provides a medical device.
  • the present disclosure provides a drug-coated medical device, including a carrier and a drug coating that partially or completely covers the carrier;
  • the drug coating is mainly obtained by coating a coating liquid including macrolide drugs and dispersants;
  • the dispersant includes water and/or organic solvents; that is, the dispersant can be only water, only organic solvents, or both water and organic solvents.
  • the organic solvent includes at least one of ethanol, acetone, methylene chloride, 1,4-dioxane, tetrahydrofuran and toluene.
  • the drug-coated medical device provided by the present disclosure can transfer sufficient drugs to the blood vessel wall during the time it is in contact with the blood vessel wall, and, for a long time after the drug-coated medical device is withdrawn, the drug-coated medical device can transfer to the blood vessel wall tissue. A certain drug concentration is still maintained.
  • the macrolide drug can be any conventional macrolide drug, which can be purchased directly.
  • Macrolides can be in crystalline form, powdery form, or granular form.
  • a system obtained by dispersing one (or more) substance in another (or more) substance is called a dispersion system.
  • the former belongs to the dispersed substance and is called a dispersoid.
  • the latter plays the role of accommodating the dispersed substance and is called a dispersion system.
  • Dispersant refers to a substance that serves to accommodate the dispersion.
  • the mass ratio of the macrolide drug and the dispersant is 20 to 100 (25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 can also be selected) : 100 ⁇ 6000 (You can also choose 110, 120, 150, 170, 200, 230, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1500, 1800, 2000, 2300, 2500, 2800, 3000, 4000, 5000 or 5500).
  • Adopting the above mass ratio is beneficial to obtain drug-coated medical devices with better performance.
  • the macrolide drugs include everolimus, tacrolimus, zotarolimus, rapamycin (sirolimus), temsirolimus, biolimus, 7 - At least one of O-desmethylrapamycin, desfolimus, 32-deoxyrapamycin and 42-O-(2-ethoxyethyl)rapamycin.
  • the carrier includes a drug balloon and/or a drug-eluting stent.
  • the coating liquid also includes antioxidants.
  • the antioxidants include water-soluble antioxidants and/or fat-soluble antioxidants.
  • the water-soluble antioxidant includes at least one of malic acid, chlorogenic acid, proanthocyanidins, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate and vitamin E polyethylene glycol succinate.
  • Malic acid also known as 2-hydroxysuccinic acid. There are three isomers: L-malic acid, D-malic acid and DL-malic acid. Malic acid is colorless needle-shaped crystals or white crystal powder, odorless and has a special and pleasant sour taste.
  • Chlorogenic acid is an organic compound with the chemical formula C 16 H 18 O 9 . It has antibacterial, antiviral, white blood cell-increasing, hepatoprotective and choleretic, anti-tumor, lowering blood pressure, lowering blood lipids, scavenging free radicals and stimulating the central nervous system functions.
  • Proanthocyanidins are a general name for a large class of polyphenolic compounds widely found in plants. They have strong antioxidant and free radical elimination effects.
  • Ascorbic acid also known as vitamin C and vitamin C, is a polyhydroxy compound with the chemical formula C 6 H 8 O 6 . It is white crystal or crystalline powder, odorless, sour in taste, and gradually changes color to yellowish after a long time. Easily soluble in water, acidic, slightly soluble in ethanol.
  • the chemical formula of sodium ascorbate is C 6 H 7 O 6 Na. It is a white to slightly yellowish white crystalline powder or granule, odorless and slightly salty in taste. soluble in water. Can be used as an antioxidant in food.
  • Calcium ascorbate is a white to light yellow crystalline powder, odorless, soluble in water, slightly soluble in ethanol, and insoluble in ether. It is more stable than Vc and has better antioxidant effect than Vc.
  • Calcium pantothenate is an organic substance with the chemical formula C 18 H 32 O 10 N 2 Ca, which is easily soluble in water and glycerin.
  • the fat-soluble antioxidants include vitamin E, dibutylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, tocopherol, probucol, propyl gallate and tert-butyl terephthalate. At least one kind of phenol.
  • Vitamin E is a type of fat-soluble vitamin, including four tocopherols and four tocotrienols, and is an antioxidant.
  • BHT Dibutylhydroxytoluene
  • Butylated hydroxyanisole also known as butyl anisole, tert-butyl p-hydroxyanisole, butylated hydroxyanisole, and butylated hydroxyanisole. It is white to slightly yellow crystal or waxy solid with a slight special smell. Can be used as food antioxidant.
  • Ascorbyl palmitate is an esterification product of natural ingredients such as palmitic acid and L-ascorbic acid. Its chemical formula is C 22 H 38 O 7 . It is an efficient oxygen scavenger and synergist.
  • Tocopherol is a hydrolyzate of vitamin E, which increases the antioxidant effect of cells and maintains and promotes reproductive functions. It has a certain anti-aging effect, can also improve lipid metabolism, prevent arteriosclerosis, and lower blood lipids.
  • Probucol is a white or off-white crystalline powder with a special odor. It has the effects of regulating blood lipids and resisting lipid peroxidation.
  • Propyl gallate white to light yellowish brown crystalline powder or milky white needle crystals. Odorless, slightly bitter, and the aqueous solution is tasteless. It is hygroscopic and light can promote its decomposition. Hardly soluble in water, easily soluble in hot water, ethanol, ether, propylene glycol, glycerin, cottonseed oil, peanut oil, and lard.
  • Tert-butylhydroquinone also known as tert-butylhydroquinone, abbreviated as TBHQ.
  • Tert-butylhydroquinone is white powdery crystal with a special smell. Easily soluble in ethanol and ether, soluble in grease, but insoluble in water.
  • Macrolide drugs are prone to oxidation in the air. Therefore, by adding antioxidants, the present disclosure can improve the storage stability of the product and extend the storage validity period of drug-coated medical devices.
  • the mass ratio of the antioxidant to the macrolide drug is 0.01 to 10 (0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8 or 9 can also be selected) :1.
  • the antioxidant used in the coating liquid is a water-soluble antioxidant; or, when the dispersant in the coating liquid is an organic solvent
  • the antioxidant used in the coating liquid is a fat-soluble antioxidant.
  • the antioxidant used in the coating liquid can be a water-soluble antioxidant or a fat-soluble antioxidant, or a water-soluble antioxidant can be used and a blend of fat-soluble antioxidants.
  • the coating liquid also includes polymer materials.
  • the polymer material functions as a binder (adhesive) on the one hand, and as a dispersion stabilizer on the other hand.
  • polymer materials serve as binders to improve the adhesion between the mixed material and the carrier.
  • the polymer material serves as a dispersion stabilizer so that macrolide drugs can be stably dispersed in the dispersant and facilitate coating.
  • the polymer material includes at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone and polyvinyl alcohol.
  • the mass ratio of the polymer material to the dispersant is 0.1 to 30 (0.5, 1, 2, 3, 4, 5, 6, 7, 8 or 9 can also be selected): 100 to 1000 ( Also choose from 120, 150, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800 or 900).
  • the drug coating consists of a coating liquid including macrolide drugs and a dispersant, and an additive solution including water. coated.
  • the coating liquid containing the macrolide drug and the dispersant is usually a suspension.
  • the coating liquid is made into a suspension state by stirring, vortexing, ultrasonic or homogenizing treatment (using a homogenizer), even if the solid drug in the coating liquid is small. Particles are suspended in a liquid. In this way, the macrolide drug can be evenly covered on the surface of the carrier during coating.
  • the drug coating is obtained by coating the coating liquid including macrolide drugs and the dispersant, and an additive solution including water. Because macrolide drugs are usually soluble in organic solvents, the coating liquid prepared at this time is in a solution state. When an additive solution including water is used together with the coating liquid for coating, the macrolide drug will re-precipitate when it comes into contact with water, in the form of crystals, powders or small particles. In this way, the crystal form of macrolide drugs will not be affected during the subsequent drying process.
  • the additive solution also includes water-soluble antioxidants and/or polymer materials.
  • the additive solution is mainly made of the following components in terms of parts by mass: 80 to 1200 parts of water (including but not limited to 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, The point value of any one of 115 parts, 200 parts, 500 parts, 800 parts, 1000 parts, 1100 parts or the range value between any two), water-soluble antioxidant 0 to 100 parts (including but not limited to 5 Point value or any one of 10 copies, 15 copies, 20 copies, 25 copies, 30 copies, 35 copies, 40 copies, 45 copies, 50 copies, 60 copies, 70 copies, 80 copies, 90 copies The range value between the two) and 0 to 300 parts of polymer materials (including but not limited to 10 parts, 30 parts, 50 parts, 80 parts, 100 parts, 130 parts, 150 parts, 180 parts, 200 parts, 230 parts , 250 copies, 270 copies, 290 copies, or any range value between the two).
  • 80 to 1200 parts of water including but not limited to 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, The point value
  • the mass ratio of the coating liquid and the additive solution is 1 to 7 (2, 3, 4, 5 or 6 can also be selected): 1 to 7 (2, 3, 4, 5 can also be selected or 6).
  • the coating concentration of the coating liquid is 0.05 ⁇ g/mm 2 to 50 ⁇ g/mm 2 based on macrolide drugs; including but not limited to 0.1 ⁇ g/mm 2 , 0.5 ⁇ g/mm 2 , 1 ⁇ g/mm 2 , 3 ⁇ g/mm 2 , 5 ⁇ g/mm 2 , 8 ⁇ g/mm 2 , 10 ⁇ g/mm 2 , 15 ⁇ g/mm 2 , 20 ⁇ g/ mm 2 , 25 ⁇ g/mm 2 , 30 ⁇ g/mm 2 , 35 ⁇ g/mm 2 , 40 ⁇ g/mm 2 , 45 ⁇ g/mm 2 any one point value or any range value between the two.
  • the present disclosure also provides a method for preparing a drug-coated medical device as described above, including the following steps:
  • a coating liquid including a macrolide drug and a dispersant is coated on the surface of the carrier to obtain a drug-coated medical device.
  • the preparation method provided by the present disclosure is simple, easy to implement, has a short process flow, and has mild conditions. It can not only save a lot of time, but also reduce costs, and is also suitable for mass production.
  • the present disclosure is to directly coat the drug on the surface of the carrier in the form of small particles.
  • the carrier needs to be hydrophilically pretreated, or a specific material is pre-coated on the surface of the carrier to obtain a base coating.
  • the carrier is directly coated on the carrier. Growing drug crystals.
  • the preparation method provided by the present disclosure is very simple to operate, has a short process flow, and is short in time. Moreover, the drug-coated medical device produced by this method can not only transfer enough drugs to the blood vessel wall, but also maintain a certain drug concentration in the blood vessel wall tissue for a long time after the drug-coated medical device is withdrawn. , optionally, 4 weeks after surgery, the drug concentration in the tissue is still above 1ng/mg, which can meet the needs of the medical field.
  • the D50 particle size of the macrolide drug is less than 200 ⁇ m; including but not limited to 190 ⁇ m, 180 ⁇ m, 170 ⁇ m, 160 ⁇ m, 150 ⁇ m, 130 ⁇ m, 110 ⁇ m, 100 ⁇ m, 80 ⁇ m, 60 ⁇ m, 50 ⁇ m, 30 ⁇ m, 20 ⁇ m, 10 ⁇ m , 5 ⁇ m, 3 ⁇ m, 1 ⁇ m, 0.5 ⁇ m, 0.3 ⁇ m, 0.1 ⁇ m, 0.05 ⁇ m any one point value or any range value between the two.
  • the coating concentration of the coating liquid is 0.05 ⁇ g/mm 2 to 50 ⁇ g/mm 2 in terms of drug; including but not limited to 0.1 ⁇ g/mm 2 , 0.5 ⁇ g/mm 2 , 1 ⁇ g/mm 2 , 3 ⁇ g /mm 2 , 5 ⁇ g/mm 2 , 8 ⁇ g/mm 2 , 10 ⁇ g/mm 2 , 15 ⁇ g/mm 2 , 20 ⁇ g/mm 2 , 25 ⁇ g/ mm 2 , 30 ⁇ g/mm 2 , 35 ⁇ g/mm 2 , 40 ⁇ g/mm 2 , 45 ⁇ g /mm A point value of any one of 2 or a range value between any two.
  • the coating method includes at least one of spraying, dipping, dripping and brushing.
  • the spraying includes ultrasonic spraying.
  • Ultrasonic spraying also known as ultrasonic spraying, refers to a spraying process using ultrasonic atomization technology.
  • the material it sprays can be a solution or suspension.
  • Ultrasonic spraying has the advantages of high coating uniformity, high raw material utilization, less spatter, and easy control of the spray amount.
  • the steps of drying, packaging and sterilization are also included in sequence.
  • the coating method includes the following steps:
  • a coating liquid including a macrolide drug and a dispersant and an additive solution including water are simultaneously coated on the surface of the carrier.
  • the additive solution also includes water-soluble antioxidants and/or polymer materials.
  • the water-soluble antioxidant includes at least one of malic acid, chlorogenic acid, proanthocyanidins, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate and vitamin E polyethylene glycol succinate;
  • the high The molecular material includes at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone and polyvinyl alcohol.
  • simultaneous coating means that the coating liquid and the additive solution are coated on the surface of the carrier at the same time, and the coating positions of the coating liquid and the additive solution are the same.
  • spraying the coating liquid and the additive solution are sprayed onto the surface of the carrier from two directions at the same time, and an intersection is formed on the surface of the carrier during spraying.
  • macrolide drugs will re-precipitate when they come into contact with water, so the crystal form of the macrolide drugs will not be affected during the subsequent drying process, thus ensuring the efficacy of the drug.
  • the temperature of the coating liquid and/or the additive solution is less than 70°C, including but not limited to any one of 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, and 5°C. or the pip value or any range value between the two.
  • the present disclosure also provides a drug-coated medical device as described above, or a drug-coated medical device prepared by the method for preparing a drug-coated medical device as described above, which can be used to treat atherosclerotic diseases and prevent restenosis. and applications in drugs or medical devices that prevent local tissue proliferation.
  • the present disclosure also provides a drug coating, which is composed of a macrolide drug and a water-soluble antioxidant.
  • the macrolide drugs include everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-desmethyl At least one of rapamycin, desfolimus, 32-deoxyrapamycin and 42-O-(2-ethoxyethyl)rapamycin;
  • the water-soluble antioxidant includes at least one of malic acid, chlorogenic acid, proanthocyanidins, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate and vitamin E polyethylene glycol succinate;
  • the mass ratio of the water-soluble antioxidant to the macrolide drug is 0.01 to 10 (0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8 or 9):1.
  • the present disclosure also provides a medical device including a drug coating as described above.
  • the drug-coated medical device provided by the present disclosure can transfer sufficient drugs to the blood vessel wall during the process of contact with the blood vessel wall, and the drug-coated medical device can remain on the blood vessel wall for a long time after the drug-coated medical device is withdrawn. A certain drug concentration is still maintained in the tissue.
  • the preparation method of drug-coated medical devices provided by the present disclosure has the advantages of simple operation, mild conditions, short process flow, short time consumption, reduced cost, and is suitable for mass production.
  • the preparation method of drug-coated medical devices greatly simplifies the process by simultaneously applying a coating liquid containing macrolide drugs and dispersants and an additive solution including water to the carrier surface. Under the premise of the preparation process, the drug-coated medical device can still maintain a high drug concentration in the blood vessel wall tissue for a long time after it is withdrawn.
  • Figure 1 is an SEM image of the drug-coated medical device provided in Example 1 of the present disclosure
  • Figure 2 is an SEM image of the drug-coated medical device provided in Example 2 of the present disclosure.
  • the preparation method of the drug-coated medical device includes the following steps:
  • a suspension (suspension) containing macrolide drugs and water is coated on the carrier surface to obtain a drug-coated medical device.
  • the suspension also includes water-soluble antioxidants and/or polymer materials.
  • the preparation method of the drug-coated medical device includes the following steps:
  • a mixed solution containing macrolide drugs and an organic solvent, and an additive solution containing water are simultaneously coated on the surface of the carrier, and the coating areas of the mixed solution and the additive solution are overlapped to obtain a drug coating. layer of medical devices.
  • the mixed solution also includes fat-soluble antioxidants.
  • the additive solution also includes water-soluble antioxidants and/or polymer materials.
  • this embodiment also obtained a drug coating composed of a macrolide drug (sirolimus) and ascorbic acid.
  • sirolimus (D50 particle size is less than 200 ⁇ m, manufacturer is Sino-American Huadong Pharmaceutical Co., Ltd.) and dissolve it in 1000 mg of ethanol to obtain a coating liquid (temperature is 25°C).
  • the above-mentioned coating liquid and additive solution are simultaneously ultrasonically sprayed on the surface of the drug balloon to form a white powder coating, and the concentration of sirolimus on the surface of the drug balloon reaches 2.5 ⁇ g/mm 2 and the concentration of L-malic acid is 1.3 ⁇ g/mm 2 . After drying, a drug-coated medical device is obtained.
  • this embodiment also obtained a drug coating composed of a macrolide drug (sirolimus) and L-malic acid.
  • sirolimus (D50 particle size is less than 200 ⁇ m, manufacturer is Xinchang Pharmaceutical Factory) and dissolve it in 5000 mg of acetone to obtain a coating liquid (temperature is 35°C).
  • the above-mentioned coating liquid and additive solution are simultaneously ultrasonically sprayed on the surface of the drug balloon to form a white powder coating, and the concentration of sirolimus on the surface of the drug balloon reaches 5 ⁇ g/mm 2 and the concentration of L-malic acid is 4.8 ⁇ g/mm 2 . After drying, a drug-coated medical device is obtained.
  • tacrolimus (D50 particle size is less than 200 ⁇ m, manufacturer is Jinan Jiage Biotechnology Co., Ltd.) and dissolve it in 100 mg of methylene chloride, then add 150 mg of vitamin E to it to obtain a coating liquid (temperature is 20°C ).
  • the above-mentioned coating solution and 200 mg of distilled water were simultaneously ultrasonically sprayed on the surface of the drug-eluting stent to form a white powder coating, and the concentration of sirolimus on the surface of the drug-eluting stent reached 8 ⁇ g/mm 2 . After drying, a drug-coated medical device is obtained.
  • tacrolimus (D50 particle size is less than 200 ⁇ m, manufacturer is Hisun Pharmaceutical) and dissolve it in 1000 mg of toluene to obtain a coating liquid (temperature: 25°C).
  • the above-mentioned coating liquid and additive solution are simultaneously ultrasonically sprayed on the surface of the drug balloon to form a white powder coating, and the concentration of sirolimus on the surface of the drug balloon reaches 2 ⁇ g/mm 2 and the concentration of L-malic acid is 1 ⁇ g/mm 2 and the concentration of carboxymethylcellulose is 3 ⁇ g/mm 2 . After drying, a drug-coated medical device is obtained.
  • this embodiment also obtained a drug coating composed of a macrolide drug (rapamycin) and chlorogenic acid.
  • the preparation method of the drug-coated medical device provided in this comparative example is basically the same as that of Example 1, except that distilled water is replaced with ethanol of equal mass.
  • the preparation method of the drug-coated medical device provided in this comparative example is basically the same as that in Example 1, except that the D50 particle size of sirolimus is replaced by greater than 200 ⁇ m.
  • the preparation method of the drug-coated medical device provided in this comparative example is basically the same as that in Example 1, except that the mass of sirolimus is replaced by 100 mg.
  • the preparation method of the drug-coated medical device provided in this comparative example is basically the same as that of Example 3. The only difference is that the step in Example 3 of "simultaneously ultrasonically spraying the above-mentioned coating liquid and additive solution on the surface of the drug balloon" Replace it with "After mixing the above coating liquid and additive solution evenly, ultrasonically spray it on the surface of the drug balloon.”
  • the drug-coated medical devices prepared in the above embodiments and comparative examples were used for animal experiments.
  • the method was as follows: under the guidance of DSA angiography (digital subtraction angiography), they were sent to the coronary arteries of pigs and expanded at 6 atmospheres for 60 seconds. Then relieve the pressure and withdraw the drug-coated medical device. After 4 weeks of feeding, they were sacrificed. The coronary arteries of the experimental animals were weighed, homogenized, extracted, and the drug concentration in the tissue was measured using a liquid chromatography-mass spectrometry instrument. The results are shown in Table 1 below:
  • Example 1 Group Drug concentration in tissue (ng/mg) Example 1 1.25 ⁇ 0.81 Example 2 2.90 ⁇ 1.91 Example 3 6.09 ⁇ 4.78 Example 4 2.05 ⁇ 2.01 Example 5 5.30 ⁇ 4.79 Example 6 2.3 ⁇ 1.8 Example 7 3.6 ⁇ 2.1
  • Example 8 1.9 ⁇ 1.2
  • Example 9 3.1 ⁇ 1.8
  • Example 10 4.2 ⁇ 3.8 Comparative example 1 below detection limit Comparative example 2 below detection limit Comparative example 3 1.51 ⁇ 1.01 Comparative example 4 below detection limit

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Abstract

本公开涉及医疗器械技术领域，具体而言，涉及一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用。药物涂层医疗器械包括载体以及部分或完全覆盖所述载体的药物涂层；其中，所述药物涂层主要由包括大环内酯类药物和分散剂的涂覆液涂覆得到；所述分散剂包括水和/或有机溶剂，所述有机溶剂包括乙醇、丙酮、二氯甲烷、1,4-二氧六环、四氢呋喃和甲苯中的至少一种。本公开所提供的药物涂层医疗器械在与血管壁接触的过程中能够将足够的药物转载到血管壁上，并且在该药物涂层医疗器械撤出后较长时间内在血管壁组织中仍然维持有一定药物浓度。

Description

一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用
相关申请的交叉引用
本公开要求于2022年03月21日提交中国专利局的申请号为CN202210276877.8、名称为“一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用”的中国专利申请的优先权，其全部内容通过引用结合在本公开中。
技术领域
本公开涉及医疗器械技术领域，具体而言，涉及一种药物涂层医疗器械及其制备方法与应用、药物涂层及其应用。
背景技术
大环内酯类药物如西罗莫斯，依维莫斯，他克莫司和佐他莫司等已被证明具有较好的抗增殖作用，可负载于血管内植入器械的表面，通过一定时间的缓慢释放可以起到抑制血管平滑肌细胞增殖，减少再狭窄的作用。然而，由于血管内植入物的存在，也会带来一系列的负面作用。因此，人们期望一方面能够在开通闭塞或狭窄的病变血管的同时将这些药物输送到病变血管处；同时在治疗结束器械撤出后，又能使这些药物在病变血管处停留足够长的时间，以起到防止再狭窄的作用。
由于这类药物本身在血液中有一定的溶解度，因此在短暂的器械表面与血管壁接触的治疗时间(通常不大于60秒)内，需要将足够剂量的药物转移到血管壁内，并使之在术后较长时间(比如4周)内仍然维持一定的有效组织浓度，这在技术上有较大的挑战。同时，根据已有文献的记载，在术后4周，组织中药物浓度在1ng/mg以上，即可以保证有效防止再狭窄的发生。因此，提供一种在短暂的器械表面与血管壁接触的治疗时间内能够将足够剂量的药物转移到血管壁内，并且在术后较长时间内仍然维持一定的有效组织浓度的负载有药物的医疗器械具有重要意义。
此外，现有技术中，负载有药物的医疗器械的制备方法往往很复杂，存在工艺流程长、浪费时间和人力以及成本高等缺点。
发明内容
本公开提供一种药物涂层医疗器械，在该药物涂层医疗器械与血管壁接触的时间中，能够将足够的药物转载到血管壁上，并且在该药物涂层医疗器械撤出后较长时间内 在血管壁组织中仍然维持有一定药物浓度。
本公开提供一种药物涂层医疗器械的制备方法，该制备方法具有操作简单、条件温和、工艺流程短、节省时间、降低成本以及适合大批量生产等优点。
本公开提供如上所述的药物涂层医疗器械在制备治疗动脉粥样硬化疾病、防止再狭窄以及防止局部组织增生的药物或医疗器械中的应用。
本公开提供一种药物涂层。
本公开提供一种医疗器械。
本公开提供了一种药物涂层医疗器械，包括载体以及部分或完全覆盖所述载体的药物涂层；
其中，所述药物涂层主要由包括大环内酯类药物和分散剂的涂覆液经过涂覆得到；
所述分散剂包括水和/或有机溶剂；即，分散剂可以只选择水，也可以只选择有机溶剂，或同时选择水和有机溶剂。
所述有机溶剂包括乙醇、丙酮、二氯甲烷、1,4-二氧六环、四氢呋喃和甲苯中的至少一种。
本公开所提供的药物涂层医疗器械在与血管壁接触的时间中能够将足够的药物转载到血管壁上，并且，在该药物涂层医疗器械撤出后较长时间内，在血管壁组织中仍然维持有一定药物浓度。
其中，大环内酯类药物可采用任意的、常规的大环内酯类药物，可直接通过购买获得。大环内酯类药物的状态可以是结晶态，也可以是粉末状、颗粒状。
把一种(或多种)物质分散在另一种(或多种)物质中得到的体系叫做分散系，前者属于被分散物质，称作分散质，后者起容纳分散质的作用，称作分散剂。在本公开中，所述分散剂即指起容纳分散质作用的物质。
可选地，所述大环内酯类药物和所述分散剂的质量比为20～100(还可以选择25、30、35、40、45、50、60、70、80、90或100)：100～6000(还可以选择110、120、150、170、200、230、250、300、400、500、600、700、800、900、1000、1300、1500、1800、2000、2300、2500、2800、3000、4000、5000或5500)。
采用上述质量比有利于获得性能更好的药物涂层医疗器械。
可选地，所述大环内酯类药物包括依维莫司、他克莫司、佐他莫司、雷帕霉素(西 罗莫司)、坦西莫司、比欧莫司、7-O-去甲基雷帕霉素、地磷莫司、32-脱氧雷帕霉素和42-O-(2-乙氧基乙基)雷帕霉素中的至少一种。
可选地，所述载体包括药物球囊和/或药物洗脱支架。
可选地，所述涂覆液中还包括抗氧化剂。
可选地，所述抗氧化剂包括水溶性抗氧化剂和/或脂溶性抗氧化剂。
可选地，所述水溶性抗氧化剂包括苹果酸、绿原酸、原花青素、抗坏血酸、抗坏血酸钠、抗坏血酸钙、抗坏血酸钾、泛酸钙和维生素E聚乙二醇琥珀酸酯中的至少一种。
苹果酸，又名2-羟基丁二酸。有L-苹果酸、D-苹果酸和DL-苹果酸3种异构体。苹果酸为无色针状结晶，或白色晶体粉末，无臭，有特殊愉快的酸味。
绿原酸是一种有机化合物，化学式为C 16H 18O 9。其具有抗菌、抗病毒、增高白血球、保肝利胆、抗肿瘤、降血压、降血脂、清除自由基和兴奋中枢神经系统等作用。
原花青素是植物中广泛存在的一大类多酚类化合物的总称，具有强抗氧化、消除自由基的作用。
抗坏血酸又称维他命C、维生素C，是一种多羟基化合物，化学式为C 6H 8O 6。其为白色结晶或结晶性粉末，无臭，味酸，久置色渐变微黄。在水中易溶，呈酸性，在乙醇中略溶。
抗坏血酸钠化学式为C 6H 7O 6Na，白色至微黄白色结晶性粉末或颗粒，无臭，味稍咸。易溶于水。可用作食品的抗氧化剂。
抗坏血酸钙，为白色至浅黄色结晶性粉末，无臭，溶于水，稍溶于乙醇，不溶于乙醚。其比Vc稳定，且抗氧化作用优于Vc。
泛酸钙是一种有机物，化学式为C 18H 32O 10N 2Ca，易溶于水和甘油。
可选地，所述脂溶性抗氧化剂包括维生素E、二丁基羟基甲苯、丁基羟基苯甲醚、抗坏血酸棕榈酸酯、生育酚、普罗布考、没食子酸丙酯和叔丁基对苯二酚中的至少一种。
维生素E是一类脂溶性维生素，包括了四种生育酚和四种生育三烯酚，是一种抗氧化剂。
二丁基羟基甲苯(BHT)具有抗氧化和防腐等作用。
丁基羟基苯甲醚，又称丁基大茴香醚、叔丁基对羟基茴香醚、丁基化羟基苯甲醚、丁羟基茴香醚。为白色至微黄色结晶或蜡状固体，略有特殊气味。可用作食品抗氧化剂。
抗坏血酸棕榈酸酯为棕榈酸与L-抗坏血酸等天然成分酯化而成，其化学式为C 22H 38O 7，是一种高效的氧清除剂和增效剂。
生育酚是维生素E的水解产物，增加细胞的抗氧化作用，维持和促进生殖机能。具有一定的抗老化作用，还能改善脂质代谢，防止动脉硬化，降低血脂。
普罗布考为白色或类白色的结晶性粉末；有特臭。具有调血脂和抗脂质过氧化作用。
没食子酸丙酯，白色至淡黄褐色结晶性粉末或乳白色针状结晶。无臭，稍具苦味，水溶液无味。有吸湿性，光照可促进其分解。难溶于水，易溶于热水、乙醇、乙醚、丙二醇、甘油、棉籽油、花生油、猪油。
叔丁基对苯二酚，又名叔丁基氢醌，简称TBHQ。叔丁基对苯二酚为白色粉状晶体，有特殊气味。易溶于乙醇和乙醚，可溶于油脂，不溶于水。
大环内酯类药物在空气中容易发生氧化，因此，本公开通过加入抗氧化剂，可以提高产品的储存稳定性，延长药物涂层医疗器械的储存有效期。
可选地，所述抗氧化剂与所述大环内酯类药物的质量比为0.01～10(还可以选择0.1、0.5、1、2、3、4、5、6、7、8或9)：1。
可选地，当所述涂覆液中的分散剂为水时，所述涂覆液中所采用的抗氧化剂为水溶性抗氧化剂；或者，当所述涂覆液中的分散剂为有机溶剂时，所述涂覆液中所采用的抗氧化剂为脂溶性抗氧化剂。
当涂覆液中的分散剂同时采用水和有机溶剂时，所述涂覆液中所采用的抗氧化剂可以添加水溶性抗氧化剂或脂溶性抗氧化剂中的一种，也可以采用水溶性抗氧化剂和脂溶性抗氧化剂的混合物。
可选地，所述涂覆液中还包括高分子材料。
高分子材料一方面起到粘结剂(粘合剂)的作用，另一方面起到分散稳定剂的作用。
其中，高分子材料作为粘结剂具有提高混合物料与载体粘附性的作用。
同时，高分子材料作为分散稳定剂使得大环内酯类药物可以稳定地分散在分散剂中，便于涂覆。
可选地，所述高分子材料包括聚乙二醇、聚氧化乙烯、透明质酸、羧甲基纤维素、胶原、聚乙烯吡咯烷酮和聚乙烯醇中的至少一种。
可选地，所述高分子材料与所述分散剂的质量比为0.1～30(还可以选择0.5、1、2、3、4、5、6、7、8或9)：100～1000(还可以选择120、150、180、200、250、300、 350、400、450、500、600、700、800或900)。
可选地，当所述涂覆液中的所述分散剂为有机溶剂时，所述药物涂层由包括大环内酯类药物和分散剂的涂覆液，以及，包括水的添加剂溶液共同涂覆得到。
当分散剂采用水时，由于大部分大环内酯类药物不易溶于水，因此含有大环内酯类药物和分散剂的涂覆液通常为悬浮液。在本公开一些可选的实施方式中，通过搅拌、涡旋、超声或均质处理(采用均质机进行)等手段使涂覆液呈现悬浊液状态，即使涂覆液中的固体药物小颗粒悬浮于液体中。这样在进行涂覆时能使大环内酯类药物均匀覆盖在载体的表面。
当涂覆液中的分散剂采用有机溶剂时，药物涂层由包括大环内酯类药物和分散剂的涂覆液，以及，包括水的添加剂溶液共同涂覆得到。因为通常情况下大环内酯类药物能溶于有机溶剂，因此此时制得的涂覆液为溶液状态。而采用包括水的添加剂溶液与涂覆液共同进行涂覆，在进行涂覆时大环内酯类药物在接触水时会重新析出，呈结晶状、粉末状或小颗粒状。这样后续干燥过程中不会影响大环内酯类药物的晶型。
可选地，所述添加剂溶液中还包括水溶性抗氧化剂和/或高分子材料。
可选地，所述添加剂溶液主要由按照质量份数计的如下组分制成：水80～1200份(包括但不限于85份、90份、95份、100份、105份、110份、115份、200份、500份、800份、1000份、1100份中的任意一者的点值或任意两者之间的范围值)，水溶性抗氧化剂0～100份(包括但不限于5份、10份、15份、20份、25份、30份、35份、40份、45份、50份、60份、70份、80份、90份中的任意一者的点值或任意两者之间的范围值)和高分子材料0～300份(包括但不限于10份、30份、50份、80份、100份、130份、150份、180份、200份、230份、250份、270份、290份中的任意一者的点值或任意两者之间的范围值)。
可选地，所述涂覆液和所述添加剂溶液的质量比为1～7(还可以选择2、3、4、5或6)：1～7(还可以选择2、3、4、5或6)。
在本公开一些可选的实施方式中，所述涂覆液的涂覆浓度以大环内酯类药物计为0.05μg/mm 2～50μg/mm 2；包括但不限于0.1μg/mm 2、0.5μg/mm 2、1μg/mm 2、3μg/mm 2、5μg/mm 2、8μg/mm 2、10μg/mm 2、15μg/mm 2、20μg/mm 2、25μg/mm 2、30μg/mm 2、35μg/mm 2、40μg/mm 2、45μg/mm 2中的任意一者的点值或任意两者之间的范围值。
本公开还提供了如上所述的药物涂层医疗器械的制备方法，包括如下步骤：
将包括大环内酯类药物和分散剂的涂覆液涂覆在所述载体表面，得到药物涂层医疗 器械。
本公开所提供的制备方法简单、易行、工艺流程短、条件温和，不仅能够节省大量时间，而且能够降低成本，还适合大批量生产。
可选地，本公开是将药物以小颗粒的形式直接涂覆在载体表面。
在现有技术中，药物涂层医疗器械的制备方法往往很复杂，例如需对载体进行亲水预处理，或者预先在载体表面涂覆特定的材料得到底涂层，再例如，直接在载体上生长药物晶体。
而本公开所提供的制备方法操作非常简单，工艺流程短，耗时短。并且该方法制得的药物涂层医疗器械，不仅能够将足够的药物转载到血管壁上，而且在该药物涂层医疗器械撤出后，较长时间内在血管壁组织中仍然维持有一定药物浓度，可选地，在术后4周后，组织中的药物浓度仍在1ng/mg以上，能够满足医学领域的需求。
可选地，所述大环内酯类药物的D50粒径小于200μm；包括但不限于190μm、180μm、170μm、160μm、150μm、130μm、110μm、100μm、80μm、60μm、50μm、30μm、20μm、10μm、5μm、3μm、1μm、0.5μm、0.3μm、0.1μm、0.05μm中的任意一者的点值或任意两者之间的范围值。
可选地，所述涂覆液的涂覆浓度以药物计为0.05μg/mm 2～50μg/mm 2；包括但不限于0.1μg/mm 2、0.5μg/mm 2、1μg/mm 2、3μg/mm 2、5μg/mm 2、8μg/mm 2、10μg/mm 2、15μg/mm 2、20μg/mm 2、25μg/mm 2、30μg/mm 2、35μg/mm 2、40μg/mm 2、45μg/mm 2中的任意一者的点值或任意两者之间的范围值。
可选地，所述涂覆的方法包括喷涂、浸涂、滴涂和刷涂中的至少一种。
可选地，所述喷涂包括超声喷涂。
超声喷涂，又名超声波喷涂，是指利用超声波雾化技术进行的喷涂工艺。其喷涂的材料可以是溶液或悬浮液。超声波喷涂具有涂层均匀度高、原料利用率高、飞溅少、易于控制喷涂量等优点。
可选地，在所述涂覆之后，还包括依次进行干燥、包装和灭菌的步骤。
可选地，当所述涂覆液中的所述分散剂为有机溶剂时，所述涂覆的方法包括如下步骤：
将包括大环内酯类药物和分散剂的涂覆液以及包括水的添加剂溶液同时涂覆至所述载体的表面。
可选地，所述添加剂溶液中还包括水溶性抗氧化剂和/或高分子材料。其中，所述 水溶性抗氧化剂包括苹果酸、绿原酸、原花青素、抗坏血酸、抗坏血酸钠、抗坏血酸钙、抗坏血酸钾、泛酸钙和维生素E聚乙二醇琥珀酸酯中的至少一种；所述高分子材料包括聚乙二醇、聚氧化乙烯、透明质酸、羧甲基纤维素、胶原、聚乙烯吡咯烷酮和聚乙烯醇中的至少一种。
在本公开中，同时涂覆是指涂覆液和添加剂溶液同时被涂覆在载体的表面，并且涂覆液和添加剂溶液的涂覆位置相同。当采用喷涂时，涂覆液和添加剂溶液由两个方向同时向载体表面进行喷涂，且在喷涂的时候在载体的表面形成交叉点。这样大环内酯类药物在接触水时会重新析出，因此在后续干燥过程中不会影响大环内酯类药物的晶型，从而有利于保证药效。
可选地，所述涂覆液和/或所述添加剂溶液的温度小于70℃，包括但不限于60℃、50℃、40℃、30℃、20℃、10℃、5℃中的任意一者的点值或任意两者之间的范围值。
本公开还提供了如上所述的药物涂层医疗器械，或者，如上所述的药物涂层医疗器械的制备方法所制得的药物涂层医疗器械在制备治疗动脉粥样硬化疾病、防止再狭窄以及防止局部组织增生的药物或医疗器械中的应用。
本公开还提供了一种药物涂层，所述药物涂层由大环内酯类药物和水溶性抗氧化剂组成。
可选地，所述大环内酯类药物包括依维莫司、他克莫司、佐他莫司、雷帕霉素、坦西莫司、比欧莫司、7-O-去甲基雷帕霉素、地磷莫司、32-脱氧雷帕霉素和42-O-(2-乙氧基乙基)雷帕霉素中的至少一种；
可选地，所述水溶性抗氧化剂包括苹果酸、绿原酸、原花青素、抗坏血酸、抗坏血酸钠、抗坏血酸钙、抗坏血酸钾、泛酸钙和维生素E聚乙二醇琥珀酸酯中的至少一种；
可选地，所述水溶性抗氧化剂与所述大环内酯类药物的质量比为0.01～10(还可以选择0.1、0.5、1、2、3、4、5、6、7、8或9)：1。
本公开还提供了一种医疗器械，包括如上所述的药物涂层。
与现有技术相比，本公开的有益效果为：
(1)本公开所提供的药物涂层医疗器械，在与血管壁接触的过程中能够将足够的药物转载到血管壁上，并且在该药物涂层医疗器械撤出后较长时间内在血管壁组织中仍然维持有一定药物浓度。
(2)本公开所提供的药物涂层医疗器械的制备方法，具有操作简单、条件温和、 工艺流程短、耗时短、降低成本以及适合大批量生产等优点。
(3)本公开所提供的药物涂层医疗器械的制备方法，通过将含有大环内酯类药物和分散剂的涂覆液以及包括水的添加剂溶液同时涂覆至载体表面，在大大简化了制备工艺的前提下，仍能使药物涂层医疗器械撤出后较长时间内在血管壁组织中维持较高的药物浓度。
附图说明
为了更清楚地说明本公开实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本公开的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本公开实施例1提供的药物涂层医疗器械的SEM图；
图2为本公开实施例2提供的药物涂层医疗器械的SEM图。
具体实施方式
下面将结合实施方式对本公开的技术方案进行清楚、完整地描述，但是本领域技术人员将会理解，下列所描述的实施例是本公开一部分实施例，而不是全部的实施例，仅用于说明本公开，而不应视为限制本公开的范围。基于本公开中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本公开保护的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
在本公开一实施方式中，所述药物涂层医疗器械的制备方法包括如下步骤：
将含有大环内酯类药物和水的悬浊液(悬浮液)涂覆在载体表面，得到药物涂层医疗器械。
可选地，所述悬浊液中还包括水溶性抗氧化剂和/或高分子材料。
在本公开另一实施方式中，所述药物涂层医疗器械的制备方法包括如下步骤：
将含有大环内酯类药物和有机溶剂的混合溶液，以及，含有水的添加剂溶液同时涂覆在载体表面，并使所述混合溶液和所述添加剂溶液的涂覆面积相重合，得到药物涂层医疗器械。
可选地，所述混合溶液中还包括脂溶性抗氧化剂。
可选地，所述添加剂溶液中还包括水溶性抗氧化剂和/或高分子材料。
本公开以下各实施例和对比例中所采用的西罗莫司、依维莫司、他克莫司均是通过购买得到。
实施例
实施例1
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在1000mg蒸馏水中添加30mg西罗莫司(D50粒径小于200μm，生产厂家为华北制药)，通过超声震荡使之形成稳定的悬浮液(悬浮液的温度为20℃)。然后取上述悬浮液超声喷涂于药物球囊表面，使药物球囊表面的药物浓度为4μg/mm 2，干燥后，得到药物涂层医疗器械。
对该药物涂层医疗器械进行SEM检测，测试结果如图1所示。从图1能够看出，药物在器械表面呈颗粒状分布。
实施例2
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在1000mg蒸馏水中添加30mg抗坏血酸，搅拌使之完全溶解，再向其中加入25mg西罗莫司(D50粒径小于200μm，生产厂家为武汉纽拜尔医药科技有限公司)，用均质机高速搅拌使之形成悬浮液(悬浮液的温度为25℃)，将该悬浮液置于超声清洗机中震荡使之保持稳定悬浮状态。
取上述悬浮液刷涂于药物球囊表面，使药物球囊表面的药物浓度为3μg/mm 2。经过干燥后，得到药物涂层医疗器械。
即，本实施例还得到了一种药物涂层，该药物涂层由大环内酯类药物(西罗莫司)和抗坏血酸组成。
对该药物涂层医疗器械进行SEM检测，测试结果如图2所示。从图2能够看出，药物在器械表面呈明显的颗粒状分布。
实施例3
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
称取30mg西罗莫司(D50粒径小于200μm，生产厂家为中美华东制药有限公司)溶于1000mg乙醇中，得到涂覆液(温度为25℃)。
在1000mg蒸馏水中添加50mg L-苹果酸，搅拌使之完全溶解，得到添加剂溶液(温度为25℃)。
将上述涂覆液和添加剂溶液同时超声喷涂在药物球囊表面，形成白色粉末状涂层，并使药物球囊表面的西罗莫司药物浓度达到2.5μg/mm 2，L-苹果酸的浓度为1.3μg/mm 2。干燥后，得到药物涂层医疗器械。
即，本实施例还得到了一种药物涂层，该药物涂层由大环内酯类药物(西罗莫司)和L-苹果酸组成。
实施例4
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在1000mg蒸馏水中添加25mg聚乙二醇(分子量为20000)，搅拌使之完全溶解，再向其中加入25mg西罗莫司(D50粒径小于200μm，生产厂家为海正制药)，用均质机高速搅拌使之形成稳定悬浮液(悬浮液的温度为30℃)。取上述悬浮液超声喷涂于药物球囊表面，使药物球囊表面的药物浓度为1μg/mm 2。干燥后，得到药物涂层医疗器械。
实施例5
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
称取30mg西罗莫司(D50粒径小于200μm，生产厂家为新昌制药厂)溶于5000mgmg丙酮中，得到涂覆液(温度为35℃)。
在1000mg蒸馏水中添加30mg泛酸钙，搅拌使之完全溶解，得到添加剂溶液(温度为35℃)。
将上述涂覆液和添加剂溶液同时超声喷涂在药物球囊表面，形成白色粉末状涂层，并使药物球囊表面的西罗莫司药物浓度达到5μg/mm 2，L-苹果酸的浓度为4.8μg/mm 2。干燥后，得到药物涂层医疗器械。
实施例6
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在3000mg蒸馏水中添加30mg依维莫司(D50粒径小于200μm，生产厂家为湖北九洲康达生物科技有限公司)，通过超声震荡使之形成稳定的悬浮液(悬浮液的温度为65℃)。然后将药物球囊浸没在上述悬浮液中，使药物球囊表面的依维莫司药物浓度为10μg/mm 2。再依次经过干燥、包装和灭菌后，得到药物涂层医疗器械。
实施例7
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在1000mg蒸馏水中添加100mg依维莫司(D50粒径小于200μm，生产厂家为武汉贝尔卡生物医药有限公司)、1mg透明质酸和300mg抗坏血酸钠，通过超声震荡使之 形成稳定的悬浮液(悬浮液的温度为40℃)。然后取上述悬浮液超声喷涂于药物洗脱支架表面，使药物洗脱支架表面的药物浓度为50μg/mm 2。再依次经过干燥、包装和灭菌后，得到药物涂层医疗器械。
实施例8
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
称取30mg他克莫司(D50粒径小于200μm，生产厂家为济南嘉格生物科技有限公司)溶于100mg二氯甲烷中，然后向其中加入150mg维生素E，得到涂覆液(温度为20℃)。
将上述涂覆液和200mg蒸馏水(即添加剂溶液)同时超声喷涂在药物洗脱支架表面，形成白色粉末状涂层，并使药物洗脱支架表面的西罗莫司药物浓度达到8μg/mm 2。干燥后，得到药物涂层医疗器械。
实施例9
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
称取100mg他克莫司(D50粒径小于200μm，生产厂家为海正药业)溶于1000mg甲苯中，得到涂覆液(温度为25℃)。
在1000mg蒸馏水中添加100mg L-苹果酸和250mg羧甲基纤维素，搅拌使之完全溶解，得到添加剂溶液(温度为25℃)。
将上述涂覆液和添加剂溶液同时超声喷涂在药物球囊表面，形成白色粉末状涂层，并使药物球囊表面的西罗莫司药物浓度达到2μg/mm 2，L-苹果酸的浓度为1μg/mm 2，羧甲基纤维素的浓度为3μg/mm 2。干燥后，得到药物涂层医疗器械。
实施例10
本实施例所提供的药物涂层医疗器械的制备方法包括如下步骤：
在1000mg蒸馏水中添加30mg绿原酸，搅拌使之完全溶解，再向其中加入25mg雷帕霉素(D50粒径小于200μm，生产厂家为宜宾韦希药业有限责任公司)，用均质机高速搅拌使之形成悬浮液(悬浮液的温度为25℃)，将该悬浮液置于超声清洗机中震荡使之保持稳定悬浮状态。
取上述悬浮液刷涂于药物球囊表面，使药物球囊表面的药物浓度为10μg/mm 2。经过干燥后，得到药物涂层医疗器械。
即，本实施例还得到了一种药物涂层，该药物涂层由大环内酯类药物(雷帕霉素)和绿原酸组成。
对比例1
本对比例所提供的药物涂层医疗器械的制备方法与实施例1基本相同，区别仅在于，将蒸馏水替换为等质量的乙醇。
对比例2
本对比例所提供的药物涂层医疗器械的制备方法与实施例1基本相同，区别仅在于，将西罗莫司的D50粒径替换为大于200μm。
对比例3
本对比例所提供的药物涂层医疗器械的制备方法与实施例1基本相同，区别仅在于，将西罗莫司的质量替换为100mg。
对比例4
本对比例所提供的药物涂层医疗器械的制备方法与实施例3基本相同，区别仅在于，将实施例3中的步骤“将上述涂覆液和添加剂溶液同时超声喷涂在药物球囊表面”替换为“将上述涂覆液和添加剂溶液混合均匀后，超声喷涂在药物球囊表面”。
实验例
采用上述各实施例和对比例所制得的药物涂层医疗器械进行动物实验，方法如下：在DSA造影(数字减影血管造影)引导下送到猪的冠状动脉中以6大气压扩张60秒，然后泄压，撤出药物涂层医疗器械。饲养4周后处死，取实验动物的冠状动脉称重后，通过匀浆，提取，用液相色谱-质谱联用仪器测定组织中的药物浓度，结果如下表1所示：
表1 各组组织中的药物浓度结果
组别 组织中的药物浓度(ng/mg)
实施例1 1.25±0.81
实施例2 2.90±1.91
实施例3 6.09±4.78
实施例4 2.05±2.01
实施例5 5.30±4.79
实施例6 2.3±1.8
实施例7 3.6±2.1
实施例8 1.9±1.2
实施例9 3.1±1.8
实施例10 4.2±3.8
对比例1 低于检测限
对比例2 低于检测限
对比例3 1.51±1.01
对比例4 低于检测限
从表1可以看出，本公开各个实施例组织中的药物浓度均在1ng/mg以上。因此，能够保证防止再狭窄的发生。
尽管已用实施例来说明和描述了本公开，然而应意识到，以上各实施例仅用以说明本公开的技术方案，而非对其限制；本领域的普通技术人员应当理解：在不背离本公开的精神和范围的情况下，可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本公开各实施例技术方案的范围；因此，这意味着在所附权利要求中包括属于本公开范围内的所有这些替换和修改。

Claims (13)

  1. 一种药物涂层医疗器械，其特征在于，包括载体以及部分或完全覆盖所述载体的药物涂层；
    其中，所述药物涂层主要由包括大环内酯类药物和分散剂的涂覆液涂覆得到；
    所述分散剂包括水和/或有机溶剂，所述有机溶剂包括乙醇、丙酮、二氯甲烷、1,4-二氧六环、四氢呋喃和甲苯中的至少一种。
  2. 根据权利要求1所述的药物涂层医疗器械，其特征在于，所述大环内酯类药物和所述分散剂的质量比为20～100：100～6000；
    优选地，所述大环内酯类药物包括依维莫司、他克莫司、佐他莫司、雷帕霉素、坦西莫司、比欧莫司、7-O-去甲基雷帕霉素、地磷莫司、32-脱氧雷帕霉素和42-O-(2-乙氧基乙基)雷帕霉素中的至少一种；
    优选地，所述载体包括药物球囊和/或药物洗脱支架。
  3. 根据权利要求1所述的药物涂层医疗器械，其特征在于，所述涂覆液中还包括抗氧化剂；
    优选地，所述抗氧化剂包括水溶性抗氧化剂和/或脂溶性抗氧化剂；
    优选地，所述水溶性抗氧化剂包括苹果酸、绿原酸、原花青素、抗坏血酸、抗坏血酸钠、抗坏血酸钙、抗坏血酸钾、泛酸钙和维生素E聚乙二醇琥珀酸酯中的至少一种；
    优选地，所述脂溶性抗氧化剂包括维生素E、二丁基羟基甲苯、丁基羟基苯甲醚、抗坏血酸棕榈酸酯、生育酚、普罗布考、没食子酸丙酯和叔丁基对苯二酚中的至少一种；
    优选地，所述抗氧化剂与所述大环内酯类药物的质量比为0.01～10：1；
    优选地，当所述涂覆液中的分散剂为水时，所述涂覆液中所采用的抗氧化剂为水溶性抗氧化剂；或者，当所述涂覆液中的分散剂为有机溶剂时，所述涂覆液中所采用的抗氧化剂为脂溶性抗氧化剂。
  4. 根据权利要求1所述的药物涂层医疗器械，其特征在于，所述涂覆液中还包括高分子材料；
    优选地，所述高分子材料包括聚乙二醇、聚氧化乙烯、透明质酸、羧甲基纤维素、胶原、聚乙烯吡咯烷酮和聚乙烯醇中的至少一种；
    优选地，所述高分子材料与所述分散剂的质量比为0.1～30：100～1000。
  5. 根据权利要求1～4任一项所述的药物涂层医疗器械，其特征在于，当所述涂覆液中的所述分散剂为有机溶剂时，所述药物涂层由包括大环内酯类药物和分散剂的涂覆液，以及，包括水的添加剂溶液共同涂覆得到。
  6. 根据权利要求5所述的药物涂层医疗器械，其特征在于，所述添加剂溶液中还包括水溶性抗氧化剂和/或高分子材料；
    优选地，所述添加剂溶液主要由按照质量份数计的如下组分制成：水80～1200份，水溶性抗氧化剂0～100份和高分子材料0～300份。
  7. 如权利要求1～6任一项所述的药物涂层医疗器械的制备方法，其特征在于，包括如下步骤：
    将包括大环内酯类药物和分散剂的涂覆液涂覆在所述载体表面，得到药物涂层医疗器械。
  8. 根据权利要求7所述的制备方法，其特征在于，所述大环内酯类药物的D50粒径小于200μm；
    优选地，所述涂覆液的涂覆浓度以大环内酯类药物计为0.05μg/mm 2～50μg/mm 2；
    优选地，所述涂覆的方法包括喷涂、浸涂、滴涂和刷涂中的至少一种；
    优选地，在所述涂覆之后，还包括依次进行干燥、包装和灭菌的步骤。
  9. 根据权利要求7所述的制备方法，其特征在于，所述涂覆的方法还包括如下步骤：
    将包括大环内酯类药物和分散剂的涂覆液以及包括水的添加剂溶液同时涂覆至所述载体的表面；
    优选地，所述涂覆液和/或所述添加剂溶液的温度小于70℃。
  10. 如权利要求1～6任一项所述的药物涂层医疗器械，或者，权利要求7～9任一项所述的药物涂层医疗器械的制备方法所制得的药物涂层医疗器械在制备治疗动脉粥样硬化疾病、防止再狭窄以及防止局部组织增生的药物或医疗器械中的应用。
  11. 一种药物涂层，其特征在于，所述药物涂层由大环内酯类药物和水溶性抗氧化剂组成。
  12. 根据权利要求11所述的药物涂层，其特征在于，所述大环内酯类药物包括依维莫司、他克莫司、佐他莫司、雷帕霉素、坦西莫司、比欧莫司、7-O-去甲基雷帕霉素、地磷莫司、32-脱氧雷帕霉素和42-O-(2-乙氧基乙基)雷帕霉素中的至少一种；
    优选地，所述水溶性抗氧化剂包括苹果酸、绿原酸、原花青素、抗坏血酸、抗坏血酸钠、抗坏血酸钙、抗坏血酸钾、泛酸钙和维生素E聚乙二醇琥珀酸酯中的至少一种； 优选地，所述水溶性抗氧化剂与所述大环内酯类药物的质量比为0.01～10：1。
  13. 一种医疗器械，包括如权利要求11或12所述的药物涂层。
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